Truncating Variants in NAA15 Are Associated with Variable Levels of Intellectual Disability, Autism Spectrum Disorder, and Congenital Anomalies.

TitleTruncating Variants in NAA15 Are Associated with Variable Levels of Intellectual Disability, Autism Spectrum Disorder, and Congenital Anomalies.
Publication TypeJournal Article
Year of Publication2018
AuthorsCheng, H, Dharmadhikari, AV, Varland, S, Ma, N, Domingo, D, Kleyner, R, Rope, AF, Yoon, M, Stray-Pedersen, A, Posey, JE, Crews, SR, Eldomery, MK, Akdemir, ZCoban, Lewis, AM, Sutton, VR, Rosenfeld, JA, Conboy, E, Agre, K, Xia, F, Walkiewicz, M, Longoni, M, High, FA, van Slegtenhorst, MA, Mancini, GMS, Finnila, CR, van Haeringen, A, Hollander, Nden, Ruivenkamp, C, Naidu, S, Mahida, S, Palmer, EE, Murray, L, Lim, D, Jayakar, P, Parker, MJ, Giusto, S, Stracuzzi, E, Romano, C, Beighley, JS, Bernier, RA, Küry, S, Nizon, M, Corbett, MA, Shaw, M, Gardner, A, Barnett, C, Armstrong, R, Kassahn, KS, Van Dijck, A, Vandeweyer, G, Kleefstra, T, Schieving, J, Jongmans, MJ, de Vries, BBA, Pfundt, R, Kerr, B, Rojas, SK, Boycott, KM, Person, R, Willaert, R, Eichler, EE, R Kooy, F, Yang, Y, Wu, JC, Lupski, JR, Arnesen, T, Cooper, GM, Chung, WK, Gecz, J, Stessman, HAF, Meng, L, Lyon, GJ
JournalAm J Hum Genet
Date Published2018 May 03
KeywordsAbnormalities, Multiple, Adolescent, Adult, Autism Spectrum Disorder, Cell Line, Child, Exons, Female, Gene Expression Regulation, Genetic Predisposition to Disease, Genetic Variation, Humans, Intellectual Disability, Male, Middle Aged, Mutation, N-Terminal Acetyltransferase A, N-Terminal Acetyltransferase E, Pedigree, Phenotype, RNA, Messenger, Saccharomyces cerevisiae

N-alpha-acetylation is a common co-translational protein modification that is essential for normal cell function in humans. We previously identified the genetic basis of an X-linked infantile lethal Mendelian disorder involving a c.109T>C (p.Ser37Pro) missense variant in NAA10, which encodes the catalytic subunit of the N-terminal acetyltransferase A (NatA) complex. The auxiliary subunit of the NatA complex, NAA15, is the dimeric binding partner for NAA10. Through a genotype-first approach with whole-exome or genome sequencing (WES/WGS) and targeted sequencing analysis, we identified and phenotypically characterized 38 individuals from 33 unrelated families with 25 different de novo or inherited, dominantly acting likely gene disrupting (LGD) variants in NAA15. Clinical features of affected individuals with LGD variants in NAA15 include variable levels of intellectual disability, delayed speech and motor milestones, and autism spectrum disorder. Additionally, mild craniofacial dysmorphology, congenital cardiac anomalies, and seizures are present in some subjects. RNA analysis in cell lines from two individuals showed degradation of the transcripts with LGD variants, probably as a result of nonsense-mediated decay. Functional assays in yeast confirmed a deleterious effect for two of the LGD variants in NAA15. Further supporting a mechanism of haploinsufficiency, individuals with copy-number variant (CNV) deletions involving NAA15 and surrounding genes can present with mild intellectual disability, mild dysmorphic features, motor delays, and decreased growth. We propose that defects in NatA-mediated N-terminal acetylation (NTA) lead to variable levels of neurodevelopmental disorders in humans, supporting the importance of the NatA complex in normal human development.

Alternate JournalAm J Hum Genet
PubMed ID29656860
PubMed Central IDPMC5986698
Grant ListU54 HD083091 / HD / NICHD NIH HHS / United States
U01 HG007301 / HG / NHGRI NIH HHS / United States
UM1 HG006542 / HG / NHGRI NIH HHS / United States
K08 HG008986 / HG / NHGRI NIH HHS / United States
UM1 HG007301 / HG / NHGRI NIH HHS / United States
/ WT_ / Wellcome Trust / United Kingdom
P01 HD068250 / HD / NICHD NIH HHS / United States
R01 MH101221 / MH / NIMH NIH HHS / United States
R35 GM133408 / GM / NIGMS NIH HHS / United States

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